Problem Description

The ever increasing production and use of manufactured nanoparticles in industry, research and medicine, has led to greater potential for incidental environmental exposure, as well as deliberate contact through products and therapeutics. However, the potential for cellular entry and toxicity of manufactured nanoparticles has only recently begun to be investigated.

The cell is bound by the plasma membrane, a lipid bilayer which contains opposing monolayers, or leaflets, of phospholipids with the hydrophilic head groups facing the extracellular and intracellular solutions, and the hydrophobic tails facing each other. Generally speaking three routes for nanoparticle entry into cells exist, each of which must be analysed independently before a comprehensive model can be formed. These are: (i) direct diffusion; (ii) endocytosis; and (iii) ion channels and transporter proteins.

The Study Group participants are asked to help with answering the following questions:

What are the relevant parameters that need to be considered regarding nanoparticle composition and the nano-bio interface?

Can a model for diffusion of nanoparticles across the plasma membrane be generated that is robust enough to account for all potential variables?

Can a model of nanoparticle endocytosis be generated that includes all potential trafficking
pathways?

Can nanoparticle entry through plasma membrane channels and transporters truly be excluded?

Can an integrated model describing all potential means of nanoparticle entry into cells be produced?

Study Group Report

Our aim during the study group week was to analyse the differing mechanisms of nanoparticle entry into cells, and if possible to explain the role of serum in decreasing nanoparticle association with cells. A variety of different initial models were developed.

A comparison of differing mechanisms for the entry of nanoparticles into cells indicated that receptor-mediated endocytosis is dominant.

A refined analysis of receptor-mediated endocytosis was undertaken, first considering the close packing of spherical nanoparticles on a spherical surface, and then the packing in a sphere.

A compartmental ODE model was developed in order to analyse the relative contributions of endocytosis, diffusion, and membrane disruption to nanoparticle entry into cells.

As a way to approximate the parameter values for use in the compartmental model, a method for estimating actual rates of endocytosis, and the corresponding number of nanoparticles internalised was also developed, combining both the ODE model and a logistic model.

As an initial attempt in order to understand the effect of serum on nanoparticle entry, efforts were made to analyse experimental data on cellular interactions with manufactured nanoparticles in the presence of serum and without.

Finally, a two-dimensional force based approach for the behaviour of a membrane near a nanoparticle was developed in order to model the electrostatic attraction between the charged components of the nanoparticle and the cell membrane.